There are more than 15 million people in the United States who are alcoholics and the majority of Americans drink some alcohol. The airway tissues of the lung are heavily exposed to alcohol during ingestion because alcohol is vaporized from the bronchial circulation into the exhaled air. The effects of alcohol on airway physiology are largely unknown. Our preliminary data, using whole body plethysmography in unrestrained mice, show that brief oral exposure to alcohol results in a highly significant attenuation of airway hyperresponsiveness (AHR) when compared to non-alcohol exposed mice. This novel finding was reproduced with a single intraperitoneal injection of alcohol. Because the airways are heavily exposed to the vapor phase of alcohol during drinking, alcohol modulates airway cAMP levels and airway motor tone is modulated by cAMP, we hypothesize that alcohol exposure modifies airway hyperresponsiveness through a cAMP/NO-dependent mechanism. To explore this hypothesis we will: 1) characterize alcohol-induced changes in AHR in vivo (mice) and in vitro (mouse lung slices); 2) determine the mechanism(s) responsible for alcohol-altered airway responses (mouse lung slices and cell culture); and 3) determine the effects of alcohol ingestion on AHR using spirometry in normal human subjects. These innovative studies will demonstrate how alcohol modulates airway motor tone and will provide valuable information on how alcohol alters airway physiology. [unreadable] [unreadable] [unreadable]